The metabotropic glutamate receptor subtype 5 (mGluR5) is implicated in many psychiatric disorders, including schizophrenia, mood and anxiety disorders, and cocaine addition. Despite the wealth of evidence from preclinical and psychopharmacology studies demonstrating dysfunctional glutamatergic function in these devastating neuropsychiatric disorders, however, to date there is no suitable ligand. We propose to test the feasibility of identifying a radioligand that can be developed into a radiopharmaceutical to image the mGluR5 in vivo with PET or SPECT.The mGluR5 protein structure is characterized by a large extracellular domain and seven transmembrane regions. Most ligands to date are amino acids, which bind at the extracellular domain and generally have only micromolar affinity. The best ligands reported (e.g. MPEP) are non-amino acids and bind in the transmembrane region. Our design strategy is to modify the base structure in such as ways to involve additional amino acids residues in the transmembrane region, thus increasing affinity and selectivity of mGluR5 binding. The first (R21) phase of this proposal we aim to 1) synthesize and evaluate the in vitro pharmacology of new ligands for mGluR5 that can be labeled either with C and F for PET or with I for SPECT; and 2) Radiolabel the ligands with the best pharmacological properties and measure their regional brain uptake in rodents. Compounds that localize in the appropriate brain regions will be further evaluated with pharmacological challenge to assess their vivo specificity. At the end of the this phase, definitive testing of the feasibility of this approach will have been accomplished. If the quantitative criteria defined as milestones for the R21 projects are met, the R33 component will 3) perform PET/SPECT imaging and pharmacokinetic analysis in non-human primates. 4) develop the selected radiotracer into a radiopharmaceutical, perform toxicity and safety tests in preparation for an IND application, and 5) carry out initial imaging trials in healthy human subjects. The studies proposed herein will produce the first radiotracer suitable for imaging the mGluR5 receptor in living humans and will surely serve as the gateway for exploration of the functional state of the glutamatergic system in the living human brain in health and disease.